Biology subjects

Gomberts Boneca, I.

Publications and source records attributed to Gomberts Boneca, I..

3 recordsLinked to original sources

bioRxiv2024

Myocarditis and neutrophil-mediated vascular leakage but not cytokine storm associated with fatal murine leptospirosis

Leptospirosis is a neglected re-emerging zoonosis caused by Leptospira spirochetes. Its pathophysiology remains mysterious, especially in the case of severe infection with L. interrogans. In the field of infectious diseases, the cause of death is rarely investigated in preclinical models. Here, for the first time, we identified unanticipated organ failures associated with death in a murine model of acute leptospirosis. Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed. Neither lung, liver, or kidney injury nor cytokine storm, or massive necroptosis could explain death. In contrast, severe leptospirosis was associated with high serum levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES, neutrophilia, pancreatitis and vascular damage. Unexpectedly, we demonstrated neutrophil-induced vascular permeability, making neutrophils a potential new therapeutic target. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis. These features are also found in patients, making this model a paradigm for better understanding human leptospirosis and designing novel therapeutic strategies.

immunology↗

bioRxiv2020

Escape of TLR5 Recognition by Leptospira spp: A Rationale for Atypical Endoflagella

Leptospira interrogans are invasive bacteria responsible for leptospirosis, a worldwide zoonosis. They possess two periplasmic endoflagella that allow their motility. L. interrogans are stealth pathogens that escape the innate immune responses of the NOD-like receptors NOD1/2, and the human Toll-like receptor (TLR)4, sensing peptidoglycan and lipopolysaccharide (LPS), respectively. TLR5 is another receptor of bacterial cell wall components, recognizing flagellin subunits. To study the contribution of TLR5 in the host defense against leptospires, we infected WT and TLR5 deficient mice with pathogenic L. interrogans and tracked the infection by in vivo live imaging of bioluminescent bacteria or by q-PCR. We did not identify any protective or inflammatory role of murine TLR5 to control pathogenic Leptospira. Likewise, subsequent in vitro experiments showed that infections with different live strains of L. interrogans and L. biflexa did not trigger TLR5. However, unexpectedly, heat-killed bacteria stimulated human and bovine TLR5, although barely mouse TLR5. Abolition of TLR5 recognition required extensive boiling time of the bacteria or proteinase K treatment, showing an unusual high stability of the leptospiral flagellins. Interestingly, using antimicrobial peptides to destabilize live leptospires, we detected some TLR5 activity, suggesting that TLR5 could participate in the fight against leptospires in humans or cattle. Using different Leptospira strains with mutations in flagellin proteins, we further showed that neither FlaAs nor Fcps participated in the recognition by TLR5, suggesting a role for the FlaBs. These have structural homology to Salmonella FliC, and conserved residues important for TLR5 activation, as shown by in silico analyses. Accordingly, we found that leptospires regulate the expression of FlaB mRNA according to the growth phase in vitro, and that infection with L. interrogans in hamsters and in mice downregulated the expression of the FlaBs but not the FlaAs subunits. Altogether, in contrast to different bacteria that modify their flagellin sequences to escape TLR5 recognition, our study suggests that the peculiar central localization and stability of the FlaB monomers in the periplasmic endoflagella, associated with the downregulation of FlaB subunits in hosts, constitute an efficient strategy of leptospires to escape TLR5 recognition and the immune response.

immunology↗

bioRxiv2019

D-alanylation of Teichoic Acids in Bacilli impedes the immune sensing of peptidoglycan in Drosophila

Modification of cell wall components is a prominent mean for pathogens to hinder host immune defenses. Here, using the Drosophila model, we aimed at characterizing the role of D-alanine esterification of teichoic acids (TAs) in the resistance of Bacillus thuringiensis to host defenses in vivo. We show that, by preventing cationic antimicrobial effectors-mediated bacterial lysis, this cell wall modification also limits the release of peptidoglycan immunostimulatory fragments thus impeding their sensing and the subsequent induction of the IMD- NF-{kappa}B pathway. Interestingly, we show that this strategy is also adopted by Lactobacillus plantarum, a bona fide commensal, to fine-tune its immunomodulatory potential in the Drosophila gut. Markedly, we show that the D-alanylation of TAs is essential for the resistance of L. plantarum to gut lysozyme. Altogether our data shed light on the mechanism underlying the persistence and the low immunostimulatory potential of L. plantarum in the Drosophila gut.

immunology↗